Surface expression of HSP72 by LPS‐stimulated neutrophils facilitates γδT cell‐mediated killing

Abstract

During inflammation and sepsis, accumulation of activated neutrophils causes lung tissue damage and organ failure. Effective clearance of neutrophils reduces the risk of organ failure; however, its mechanisms are poorly understood. Because lungs are rich in cdT cells, we investigated the physiological role of these cells in the protection of lung tissue from infiltrating neutrophils. In a mouse model of sepsis, we found that the lungs of survivors contained significantly higher numbers of cdT cells than those of mice that died from sepsis. The number of cdT cells correlated inversely with the number of neutrophils in the lungs and with the degree of lung tissue damage. LPS rapidly elicited the expression of heat shock protein (HSP) 72 on the surface of human neutrophils. Inhibitors of transcription, protein synthesis, and intracellular protein transport blocked HSP72 expression, indicating that de novo synthesis is required. cdT cells targeted and rapidly killed LPS-treated neutrophils through direct cell-to-cell contact. Pre-treatment with neutralizing antibodies to HSP72 diminished neutrophil killing. Our data indicate that HSP72 expression on the cell surface predisposes inflamed neutrophils to killing by cdT cells. This intercellular exchange may allow cdT cells to resolve inflammation and limit host tissue damage during sepsis.

The Ischemia-Responsive Protein 94 (Irp94) Activates Dendritic Cells through NK Cell Receptor Protein-2/NK Group 2 Member D (NKR-P2/NKG2D) Leading to Their Maturation

“…Hsp72 surface expression on stressed tumor cells also augments the cytotoxicity of NK cells (45). Recent reports provide evidence of the surface expression of Hsp90 on B cell lymphomas upon EBV infection (46), the expression of Hsp60 on stressed endothelial cells (47), and the expression of Hsp72 on neutrophils by LPS (48), suggesting the surface expression of Hsps under stressed conditions. Hsps can elicit immune responses if expressed on plasma membrane (35).…”

A heat shock protein gene (Hsp70.1) is critically involved in the generation of the immune response to myelin antigen

“…More recently, apart from their potential role in regulating cell death, hsp have been implicated in the generation of immune responses [8,9]. Hsp have been shown as potent inducers of the innate immune system through interactions with cell surface receptors, leading to enhanced expression of pro-inflammatory cytokines [10,11], chemokines [12,13], and activation of dendritic cells (DC) [14][15][16] and other immune cell types [17][18][19]. In addition, through its peptide-and protein-binding properties, hsp have been demonstrated to act as strong adjuvants in the induction of adaptive immunity towards chaperoned molecules.…”

Roles of Heat Shock Proteins and γδT Cells in Inflammation

“…Nevertheless, several recent studies have demonstrated that Hsp molecules can appear on the cell surface of normal and transformed cells (7,17,(21)(22)(23). The mechanisms by which Hsp molecules are translocated to and expressed on the cell surface are poorly understood.…”

“…In contrast to the well-defined roles of Hsp in the intracellular compartment, the functions of Hsp molecules on the cell surface of normal (28), infected (21), transformed (18,22), and apoptotic cells (23,24) (7,17,18,(29)(30)(31). Another function of Hsp may be to stabilize plasma membranes that are damaged by toxins and stress-related metabolites generated in response to infections or inflammation (32).…”

“…While the processes leading to ALI are not well understood, even less information exists on the mechanisms by which the host resolves inflammatory episodes in cases in which patients are able to recover from ALI to avoid ARDS. We have recently gained a better understanding of these mechanisms, which might lead to new strategies to reduce ARDS in trauma patients (7).…”